Standardisation is the key to the sustained, rapid and healthy development of stem cell‐based therapy

Abstract Background Stem cell‐based therapy (SCT) is an important component of regenerative therapy that brings hope to many patients. After decades of development, SCT has made significant progress in the research of various diseases, and the market size has also expanded significantly. The transition of SCT from small‐scale, customized experiments to routine clinical practice requires the assistance of standards. Many countries and international organizations around the world have developed corresponding SCT standards, which have effectively promoted the further development of the SCT industry. Methods We conducted a comprehensive literature review to introduce the clinical application progress of SCT and focus on the development status of SCT standardization. Results We first briefly introduced the types and characteristics of stem cells, and summarized the current clinical application and market development of SCT. Subsequently, we focused on the development status of SCT‐related standards as of now from three levels: the International Organization for Standardization (ISO), important international organizations, and national organizations. Finally, we provided perspectives and conclusions on the significance and challenges of SCT standardization. Conclusions Standardization plays an important role in the sustained, rapid and healthy development of SCT.


INTRODUCTION
With advances in medical technology and the improvement of quality of life, replacing or regenerating damaged tissue is becoming a reality.As an important part of regenerative medicine, stem cell-based therapy (SCT) offers new hope to patients suffering from intractable diseases.The purpose of SCT therapy is to regenerate damaged cells and tissues within a human body using stem cells' unique characteristics or, in the case of replacing damaged cells with healthy cells, to deliver exogenous stem cells into the patient's body. 1 In a biological system, stem cells are units of organisation responsible for the regeneration of different organs and tissues. 2 In the human body, stem cells can be divided into five types according to their differentiation potential: totipotent, pluripotent, multipotent, oligopotent and unipotent stem cells. 3Totipotent stem cells have the highest potential and can differentiate into any of the three germ layers or form the placenta.The fertilised oocyte and the cells that divide during the first two divisions are totipotent stem cells. 3Pluripotent stem cells (PSCs) can form cells of the three germ layers, but cannot form cells of extraembryonic structures such as the placenta.One example is embryonic stem cells (ESCs) derived from blastocysts. 4Induced PSCs (iPSCs) are derived from somatic cells that have been reprogrammed into embryonic-like states, which are also pluripotent. 4,5In addition, the researchers found that adult tissues contain a population of small stem cells that also express pluripotency markers, naming them very small embryonic-like stem cells (VSELs). 6,7Multipotent cells can differentiate from a single germ layer into multiple specific cell types, the typical representative of which are mesenchymal stem cells (MSCs). 8,9Oligopotent cells, such as common myeloid progenitor cells, can differentiate into only a few cell types depending on the tissue in which they reside. 10Unipotent cells have the lowest differentiation potential and can only differentiate along a single cell lineage, such as satellite cells of skeletal muscle. 11tem cells used for SCT are capable of self-renewal and differentiation into multiple cell lineages and can be of autologous, allogeneic or xenogeneic origin. 12Compared with differentiated cells, stem cells may be an ideal cell source for tissue regeneration because of their advantages such as easy to obtain in large quantities, high proliferation rate, and multidirectional differentiation. 2,13Stem cells also have a paracrine function, indirectly playing a regeneration and repair role by releasing bioactive factors stored in exosomes. 14,15he world's first recorded allogeneic haematopoietic stem cells (HSCs) transplantation for the treatment of leukaemia was completed in 1957. 16Since bone marrow transplantation was unknown at the time, all six patients in this study died and only two patients showed evidence of transient engraftment. 16This result indicated that the graft had failed.However, in the following two years, researchers discovered that bone marrow transplantation from healthy identical twins could be used to treat leukaemia. 179][20][21][22][23][24] It has not only improved the confidence of researchers and patients in SCT, but also promoted the rapid development of SCT market (Figure 1).
SCT involves a complex and precise process, including multiple links such as tissue collection, stem cell isolation, purification, expansion, identification testing, preservation, recovery, and auxiliary material production. 25Irregularity in any of these links may have an impact on the therapeutic effect of SCT, and then affect the development of SCT.6][27] Although SCT has broad application prospects, it has not yet achieved large-scale clinical application.When things do not work as they should, it often means that standards are absent.Standards cover a wide range of activities, which may involve product manufacturing, process management and material supply. 28The transition of SCT from small-scale, customised experiments to routine clinical practice requires standards to assist.9][30] Therefore, many countries, regions and international organisations around the world have developed corresponding SCT standards, which will strongly promote the further development of the SCT industry.This article aims to summarise the clinical application progress of SCT, and focus on the research progress of SCT standardisation.

Types and characteristics of stem cells
Clinically, there are many stem cells used for treatment in the human body, which can be divided into the following four types: ESCs, VSELs, iPSCs and adult stem cells (ASCs). 1,2,31These cells have distinct characteristics in SCT (Table 1).
ESCs are mainly obtained from the inner cell mass of blastocysts. 32,33Although ESCs are pluripotent, ethical issues, immune rejection, and the risk of teratoma as stem cells serve as natural units of selection for tissue formation F I G U R E 1 Important research progress that stem cell-based therapy (SCT) has made over the decades.These public data are derived from literature searches on PubMed (https://pubmed.ncbi.nlm.nih.gov/).hESCs, human embryonic stem cells; iPSCs, induced pluripotent stem cells; SCT, stem cell-based therapy.
0][41] However, iPSCs transplantation also carries the risk of teratoma formation due to the possibility of transplanting undifferentiated cells. 37,42herefore, during the stem cell treatment process, it is important to focus on the patient's health status to reduce the potential risks of stem cell treatment as much as possible.4][45] In contrast, VSELs have emerged as an attractive cell type.VSELs are PSCs involved in blood vessel and tissue regeneration, forming a pool of recruited stem/progenitor cells that play specific and important roles in organ repair. 6,46In human bone marrow (BM), umbilical cord blood (UCB), mobilised peripheral blood (mPB), and gonads, VSELs have been observed to exist. 7,47Nonetheless, the quiescence and limited number of VSELs make isolation of these cells challenging. 47,48VSELs have limited ability to expand in vitro.In order to stimulate the proliferation of cells without compromising their pluripotency, we need to understand their biological properties. 479][50] Among them, MSCs are the most widely used subtype, including BM, adipose, umbilical cord, amniotic membrane and other tissue sources. 50,51SCs have the characteristics of low immune rejection, and most ASCs are easy to isolate and expand.50,52,53 It should be noted that their insufficient differentiation potential prevents them from naturally crossing genetic barriers to differentiate into other lineages.54 Determining in vivo biodistribution after administration is an important research component in the development of SCT.Through different routes of administration, the biodistribution of stem cell preparations in the body changes, leading to possible changes in their therapeutic effects.Current research mainly focuses on analysing the biodistribution of MSCs in the body after administration. Intravens access is the most common route for cell transplantation. Sie MSCs are much larger in diameter than HSCs, the first obstacle after intravenous injection is the lung capillary bed.55,56 Studies have found that stem cells transplanted through veins are mainly distributed in the lungs in the early stage, and then distributed in the spleen, liver and other organs.57,58 Distribution of MSCs at usual bleeding sites was observed in patients with haemophilia A at 24 h.59 Unlike intravenous administration, intravenous administration bypasses the filtration of the lungs.Sood et al. injected labelled stem cells into the superior pancreaticoduodenal artery and splenic artery respectively through peripheral venous route or targeted route to explore appropriate administration methods for diabetic patients.60 The results show that the biodistribution of stem cells following arterial infusion is characterised by systemic delivery, lack of pulmonary capture, and selective homing and retention in the pancreas compared with the intravenous route.60 Interestingly, most of the cells migrated to the liver, spleen, and BM, with few remaining in the myocardium.[61][62][63] Homing and interstitial migration are two principal modes of stem cell trafficking, which is defined as the oriented or directed movement of a cell towards a particular anatomic destination.64 This phenomenon involves chemical attractants, adhesion molecules, and specific pathways that guide migration to specific sites or niches.64,65 By manipulating stem cell trafficking, the regeneration and repair effect of damaged tissue can be improved, and the cells may also serve as vehicles for drug delivery.64 Stem cells can not only be infused through blood vessels, but can also be injected directly into lesions.A clinical study showed that after injecting MSCs into the intervertebral disc, mesenchymal stem cells were found in the intervertebral disc with chondrocyte-like differentiation 8 months later.66 After 28 months, these cells disappeared from the disc.66 Research on the in vivo biodistribution of stem cells injected into other diseased areas such as the reproductive and urinary systems, digestive systems, and the central nervous system is still at the animal model stage, and the results of different studies are different and need to be further studied.56 Various methods including physical, chemical, and genetic modification have been explored to improve the targeted delivery of stem cells to diseased tissues.67 At the same time, limitations to these methods should also be considered, as they may induce off-target toxicity and other unintended effects on stem cells, as well as lead to transient expression of molecular targets.67,68 In order to target stem cells to specific tissues, researchers have developed a variety of corresponding stem cell delivery devices.The most studied ones are devices that apply stem cells to the heart.There are three main ways to deliver stem cells to the heart: transendocardial delivery, intracoronary delivery, and transcoronary delivery.69 Devices used for transendocardial delivery of stem cells mainly include MyoCath catheter, MyoStar catheter, Helix catheter, C-Cath catheter and Phoenix combination delivery system.Both the MyoCath catheter and the MyoStar catheter are integrated systems, meaning they are made up of a support catheter and a core.Unlike the MyoCath catheter's stainless-steel needle, the MyoStar catheter has a nitinol needle.Such two catheter systems have been used in the field of cardiac regeneration and repair.[70][71][72] Unlike the previous two catheter systems, the Helix catheter is a non-integrated system that also allows safe transplantation of stem cells to improve myocardial contractility.73 The C-Cath catheter is made of nickel-titanium alloy, which improves stem cell retention in the myocardium and ensures infusion safety and ease of use. 74 Th Phoenix combined conveyor system is an emerging piece of equipment.Using this system to perform BM laser revascularisation can improve patients' living quality.75 Devices for transcoronary delivery of stem cells are typically percutaneous transluminal coronary angioplasty catheters.These balloon catheters include 'monorail' and 'over-the-wire' catheters, with the latter being more common and requiring a guiding catheter to reach its destination.The Maverick catheter and the Cricket microinfusion catheter are both over-the-wire balloon catheters that deliver stem cells.76,77 A typical device for delivering stem cells through coronary arteries is the TransAccess catheter system, currently marketed by Philips under the name Pioneer.This catheter system is injected through transcoronary venous injection. Compaed with other catheter systems, the Pioneer catheter system has higher stability, and the injection pressure is not as easy to cause ejection as ordinary catheter systems.69,78 Applying stem cells to the central nervous system is something many clinicians aspire to achieve.Due to the large size of the damaged area of the human brain, it is challenging to complete treatment with a single cell injection.To reduce the number of punctures and increase the distribution of transplanted stem cells, Brecknell et al. 79 developed the radial branch deployment (RBD) syringe system. Th system is positioned at an angle to the guidance axis to allow stem cells to reach further targets and can also be rotated to avoid potential 'hot spot' effects.80 Subsequently, a team improved the device to meet clinical safety requirements in order to reduce the risk of accidents.81 Spinal injection also has a corresponding delivery platform, which can deliver stem cells to the spinal cord stably and safely.82,83 Clinically, stem cells can also be loaded onto cell scaffolds and transplanted to other sites through endoscopic injection, which provides more possibilities for treatment options.

Clinical application status of SCT
In order to speed up the clinical application of SCT, on the basis of the safety data from previous animal experiments, countries around the world have carried out extensive SCT clinical trials.As of December 2022, there have been over 9400 stem cell-related trials registered in a clinical trial registration site (www.clinicaltrials.gov),most of which are mainly concentrated in North America, Europe and East Asia.Although not all registered clinical trials have been conducted or have results, these data still reflect the strong appeal of SCT to researchers from all over the world (Figure 2).Although SCT has not really achieved large-scale clinical application, its clinical studies in multiple disease systems have been reported and counted.According to the statistics of the Stemcell Clinical Research Database (DB), 84 the current clinical trials of SCT involve Cardiovascular, Skeletal, Nervous, Immune, Gastrointestinal, Pulmonary, Urinary, Ophthalmic and others.Among them, most of the SCT clinical trial articles focus on the first five categories, especially the largest number of studies on cardiovascular system diseases (Figure 3).Furthermore, from 1976 to the present, these clinical trials have shown an increasing trend.It should be noted that during the 3 years from 2020 to 2022, although the number of SCT clinical trial articles is not as high as the sum of the number of articles in the previous four years, the difference is not much different (Figure 4).Considering multiple factors such as immune rejection, ethical barriers and treatment costs, the transplanted cells are mainly autologous.In addition, most trials are still in the exploratory research stage, and the number of phase III and above clinical trials is relatively small (Figure 5).Therefore, there is still a certain distance for SCT to fully realise large-scale clinical application.
Different types of stem cells have achieved different clinical translational research results.The application of ESCs is restricted by ethical considerations and strict supervision, and related research mainly uses ESCs-derived cells.6][87][88][89] In order to quickly and efficiently generate RPE cells from ESCs, researchers have developed a method for rapid directional differentiation of cells. 90The described protocol can be used for clinicalgrade cell production. 902][93] Similar to ESCs, some scholars have also explored RPE cell sheets differentiated from iPSCs to treat AMD.One year later, the patients' best-corrected visual acuity had not improved or worsened, and cystoid macular oedema was present. 94To overcome fundamental limitations of the donor-derived MSC production process, Bloor et al. 95 used iPSC-derived MSCs to treat steroidresistant acute graft versus host disease (SR-aGvHD) and found that the therapy was safe and tolerable.Interestingly, iPSCs can be used not only for treatment but also for disease modelling and drug research.IPSCs can be obtained from amyotrophic lateral sclerosis (ALS) patients with different genetic phenotypes, and the genetic background of the cells is not affected by the reprogramming process. 96Therefore, iPSCs can well assess the impact of ALS on patients and accelerate ALS in vitro modelling and drug development. 96,97Notably, transplantation of iPSCsderived glial cells rather than derived motor neurons can treat ALS by improving the neuronal environment. 96In clinical practice, ASCs are the most studied.Researchers are harnessing the regenerative capabilities of ASCs to treat many diseases such as heart, brain, pancreatic and eye diseases.Currently, ASC is the gold standard for clinical application, especially represented by MSCs. 98MSCs have promising applications due to their ease of isolation and expansion, multilineage differentiation capacity, immune modulation, homing and migration, and few ethical constraints. 3ASC-based therapies have a wide range of clinical applications, covering the treatment of diseases in cardiovascular, orthopaedic, autoimmune, neurological, metabolic and other systems. 3,98As PSCs, VSELs constitute a recruitable stem cell pool and can also play an important role in tissue repair. 46,99Studies have found that VSELs in patients with lung disease can be recruited into peripheral blood (PB) to participate in tissue repair.Recruitment of VSELs has also been detected in the PB of patients with critical limb ischaemia (CLI).These cells can differentiate towards the vascular lineage and may generate human endothelial lineage cells. 100Efforts are underway around the world to encourage the development of SCT, although this may change in the future. 101

Market development status of SCT
Robust clinical trials have led to significant market growth, and the market size of SCT has grown rapidly.According to the SCT market report released by Global Market Insight in 2021, the global SCT market size was estimated at USD 8.9 billion in 2020, with North America having the largest market share at 41.5%, which may benefit from strong government support. 102The report also predicts that with the advancement of technology and increased attention for biologics, the market size of SCT will grow at a compound annual growth rate (CAGR) of more than 10.6% from 2021 to 2027. 102,103However, the development of SCT also faces limiting factors.For example, ethical issues of PSCs and their inherent properties including tumourigenicity and immunogenicity limit their use. 4,38,104,105Additionally, inconsistencies in the stability, differentiation, and trafficking of MSCs, as well as differences between preclinical and clinical studies, pose challenges to the application of SCT. 106,107All these challenges may adversely affect the market development of SCT.

THE DEVELOPMENT STATUS OF SCT-RELATED STANDARDS
SCT has made remarkable achievements in both disease treatment and market size.However, SCT includes a complete and complicated process, involving multiple links such as cell collection, culture, transportation, and detection.Irregular operation in any link may affect the actual therapeutic effect of SCT.Therefore, establishing relevant standards for stem cell research and industry is crucial to the healthy development of SCT.Only in this way can a smooth and efficient assessment of stem cell products, production facilities, therapeutic efficacy and market trends be ensured based on sound scientific principles.

SCT-related standards by ISO
At present, the international standardisation work is mainly carried out in the International Organization for Standardization (ISO).ISO is an international standard development organisation composed of standards bodies from 167 different countries.The standards it develops are recognised by international experts around the world.9][110] It is worth noting that the document listing the various requirements and regulations for cultivating and using human and mouse PSCs is named ISO 24603, which is also the first stem cell related standard for the ISO. 1092][113][114] Third, standards specify the basic requirements and general considerations for equipment systems and auxiliary materials used in the manufacturing of cells for therapeutic use.They are applicable to any unit operating system used alone or in combination for the manufacturing of cells for therapeutic use, as well as materials used for cell processing and contact with active substances. 115,1168][119] These standards provide guarantee for the healthy development of the SCT industry.ISO standards related to cell therapy include not only published standards, but also standards under development.Among the 15 standards under development in ISO/TC 276 biotechnology, 5 standards are related to SCT.On the one hand, these standards include requirements for specific types of stem cells.For example, a document named ISO/WD 18162 specifies requirements for the biobanking of human NSCs (hNSCs), including the requirements for the differentiation, culture, characterisation, quality control, storage, thawing, and transport of hNSCs. 120It should be noted that this document applies to all organisations performing biobanking of hNSCs used for research and development in the life sciences, and does not apply to hNSCs for the purpose of in vivo application in humans, clinical applications or therapeutic use. 1202][123][124] Among them, the requirements for cell morphology analysis and viability analysis are mainly applicable to mammalian cells. 121,123Whether it is the published standards or the standards under development, they have made detailed regulations on multiple links in the SCT process.ISO standards are the culmination of the wisdom of experts around the world.They can effectively improve the standardisation of SCT, and are of great significance to the standardisation of the entire industry and human health (Table 2).

SCT-related standards by international organisations
In order to supplement and update relevant SCT standards in a timely and effective manner, some international organisations have been established to assist in the development of standards.Association for the Advancement of Blood and Biotherapies (AABB, formerly known as the American Association of Blood Banks) is an international, not-for-profit organisation representing individuals and institutions involved in the field of transfusion medicine and cellular therapies.AABB sets standards for and accredits facilities that procure, process, store and/or distribute cellular therapy products.The Standards for Cellular Therapy Services outlines the requirements for donor eligibility and collection, processing, storage, and administration for any type of cell therapy product, including UCMSCs services, HSC services, somatic cell services, and cell therapy clinical services. 125Similar to AABB, Foundation for the Accreditation of Cellular Therapy (FACT) is well established and mature in the quality management of UCMSCs.FACT is a non-profit organisation co-founded by the International Society for Cell and Gene Therapy (ISCT) and the American Society for Transplantation and Cellular Therapy (ASTCT) that sets standards for the highquality development of cell therapies.Among the standards established by FACT, those related to SCT mainly include haematopoietic cell therapy standards, 126,127 cord blood bank standards 128 and common standards. 129][128][129] FACT standards are comprehensive, covering not only all stages before clinical application of cell preparations, such as collection, processing, storage, transportation and management, but also the entire process of clinical application.ISCT not only participated in the formulation of FACT standards, but also independently developed SCT-related standards, including minimal criteria and immunological characterisation of MSCs. 130,131Similar to ISCT, the International Society for Stem Cell Research (ISSCR) has set high standards for SCT as an important international professional organisation engaged in stem cell research.][134][135] In Europe, the European Commission develops the guidance and standards related to cell transplantation through the establishment of the European Directorate for the Quality of Medicines and HealthCare (EDQM).The European Pharmacopoeia (Ph.Eur.) published by EDQM includes a number of quality control standards for cell therapy, such as cell count and viability assays, microbiological examination of cell-based preparations and production of raw materials for cell-based therapy products. 136,137he official standards published within provide the basis for quality control of SCT.In order to ensure the quality and safety of tissues and cells for the human application, EDQM has also published corresponding guidelines.The latest Guide contains not only general requirements applicable to all tissue establishments and organisations involved in the donation, procurement, testing, processing, preservation, storage and distribution of tissues and cells, but also specific guidelines and requirements for the various tissue and cell types. 138However, the SCT-related standards established in Europe cannot be fully applicable to other countries or regions.In order to achieve harmonisation of standards for drug development and regulation in a wider region, representatives of the organisations in Europe, Japan and the United States discussed and established the International Council for Harmonisation (ICH).The topics of all ICH guidelines are divided into the four categories: Quality Guidelines, Safety Guidelines, Efficacy Guidelines and Multidisciplinary Guidelines.They will ensure the development and registration of safe, effective and high-quality medicines (Table 3). 139-142

SCT-related standards by national organisations
Countries around the world are pursuing global free trade by using a single standard, but it is really not easy to achieve this goal under the current situation.On the one hand, existing international standards can hardly cover the whole process of SCT.On the other hand, the specific conditions of different countries vary significantly, and the same international standard may not apply to all countries.Therefore, on the basis of adopting ISO standards, the national standards bodies of various countries will also adjust and supplement international standards according to their actual needs in order to establish national standards.Founded in 1901, the British Standards Institution (BSI) is the world's first national standards body and a national standards body designated by the UK government.In order to promote the rapid development of stem cell research in the United Kingdom, BSI has publicly released a number of SCT-related specification documents to help improve the quality and safety of cell products, services and systems.4][145][146] Similarly, German Institute for Standardization (DIN) is an independent platform for standardisation in German and worldwide, representing German interests in international organisations.A standard published by DIN specifies the general requirements for sample containers for storing biological materials in biobanks. 147Association Francaise de Normalisation (AFNOR) represents French positions at European and international level.The 2021 survey carried out by AFNOR has revealed that France has secured second place behind Germany when it comes to the number of committees for which it has been entrusted with secretariat duties.In addition to adopting ISO and European standards, AFNOR also publishes purely French standards.As early as 1986, AFNOR published a standard for general terminology in biotechnology. 148This standard covered five aspects including terms and definitions, biobanks and biological resource centres, analytical methods, biological processes, data processing and metrology. 148hen in 2016, AFNOR published a standard, which was not a cell culture manual, but provided requirements and recommendations to allow the production of cell cultures for virological or serological diagnostics in animal health. 149he United States has established a relatively complete standardised stem for cell therapy.1][152] The American National Standards Institute (ANSI) is the sole representative of ISO in the United States, but it is not a standard development organisation.Rather, American National Standards (ANS) are developed by ANSI through the process of accrediting the procedures of standards development organisations (SDOs) and approving their documents.The SDOs that develop SCT-related standards mainly include American Society for Testing and Materials (ASTM), Clinical and Laboratory Standards Institute (CLSI) and Parenteral Drug Association (PDA).4][155][156][157][158][159][160][161] ASTM has great influence, and its standards are adopted not only by the United States but also by many countries in the world.][164] The PDA has also published the standard for cell therapy control strategies applicable to autologous and allogeneic cell therapy. 165In Asia, compared with other neighbouring countries, Japan, South Korea, and China have developed rapidly in the field of SCT in recent years, which is due to their strong government support for regenerative medicine.In Japan, Japanese Industrial Standards Committee (JISC) has published standards on biotechnology vocabulary and containers for cryopreservation of cells. 166,167In Korea, Korean Agency for Technology and Standards (KATS) has also published a general guideline of safety test for the cell-based therapeutic substances. 168The national standards published by China are relatively rich in content.0][171][172][173][174] There are also many other countries have developed national standards related to SCT, such as France, Sweden, Australia, New Zealand and so on.In addition to national standards, each country may also have group standards, industry standards and local standards, which will supplement national standards in specific areas.With the efforts of all countries in the world, the standardisation of SCT is becoming more and more complete (Table 4).

CONCLUSIONS
In the new era of regenerative medicine, the emergence of SCT represents a breakthrough development in biomedical science.Stem cells have made it possible to reverse many incurable diseases through their powerful regeneration and repair ability.After decades of development, SCT has made remarkable achievements in  clinical research and market size.The healthy and rapid development of the SCT industry is inseparable from the positive guiding role played by the corresponding standards.SCT standards include three levels: ISO standards, regional organisation standards and national standards.These developed standards have effectively coordinated drug development and regulatory standards between different countries and regions, avoided overlapping standard activities, and improved the application efficiency of stem cell-related products.However, the standardisation of SCT is still in its infancy.The development direction of standards is scattered, and there is still a lack of a complete standardised system covering all aspects of SCT, which has a negative impact on the clinical application of SCT.
With the continuous deepening and gradual maturity of stem cell related research, the construction of a standardised system for SCT has also been continuously improved.Standardisation and quality control can ensure the safety and effectiveness of SCT.It is believed that SCT will truly realise the transformation from laboratory research to large-scale clinical practice in the near future.

A U T H O R C O N T R I B U T I O N S
All authors contributed to the conception of this work.J Z wrote the manuscript; MR S, JZ W, X L and HG H revised the figure; KZ W, XY L and TZ S revised the tables; ZH L and J L reviewed and revised the full text.

A C K N O W L E D G E M E N T S
This study was supported by the Science and Technology Innovation Foundation of Dalian (2022JJ12SN045), and the Natural Science Foundation of Liaoning Province (2022-MS-322).The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare they have no conflicts of interest.

D ATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

F I G U R E 2
Number of stem cell-based therapy (SCT) clinical trials registered on ClinicalTrials.govby 2022.These public data, including basic information and numbers, are derived from stem cell-related clinical trials registered on ClinicalTrials.govas of December 2022 (https://classic.clinicaltrials.gov/).SCT, stem cell-based therapy.

F I G U R E 3 F I G U R E 4
Number of stem cell clinical trial articles in different categories of diseases on StemCreDB by 2022.These public data, including disease categories and the number of clinical trial articles, are derived from statistics on the StemCreDB as of December 2022 (https://stemcredb.net/).SCT, stem cell-based therapy; StemCreDB, stem cell clinical research database.Number of stem cell clinical trial articles in different years StemCreDB by 2022.These public data, including the number of stem cell clinical trial articles every 4 years, are derived from statistics on the StemCreDB as of December 2022 (https://stemcredb.net/).SCT, stem cell-based therapy; StemCreDB, stem cell clinical research database.There are more than 250 technical committees (TC) under ISO, which develop most ISO standards.Among them, the TC involved in the development of SCT-related standards is mainly ISO/TC 276 Biotechnology.ISO/TC 276 has published 26 standards, 12 of which are related to cell therapy.These standards include four aspects.First, these standards specify the requirements for biobanks of human BM-derived MSCs (hBMSCs), human and mouse PSCs, and human UC-derived MSCs (hUCMSCs), including the collection of biological source material and associated data, isolation, culture, characterisation, quality control, cryopreservation, storage, thawing, disposal, distribution F I G U R E 5 Number of stem cell clinical trial articles in different study phases on StemCreDB by 2022.These public data, including the number of stem cell clinical trial articles in different study phases, are derived from statistics on the StemCreDB as of December 2022 (https://stemcredb.net/).SCT, stem cell-based therapy; StemCreDB, stem cell clinical research database.

2015 PAS 157 :
Abbreviations: AFNOR, French Standardization Association; ANSI, American National Standards Institute; ASTM, American Society for Testing and Materials; BSI, British Standards Institution; CFU, colony forming unit; CLSI, Clinical and Laboratory Standards Institute; DIN, German Institute for Standardization; GB/T, China National Standards; JISC, Japanese Industrial Standards Committee; KATS, Korean Agency for Technology and Standards; NF, Norme Française; PAS, publicly available specification; PDA, parenteral drug association, rhBMP-2, recombinant human bone morphogenetic protein-2; SAC, Standardization Administration of China; SCT, stem cell-based therapy.

TA B L E 1 Types and characteristics of stem cells used in SCT. Types Potency Main sources Isolation/expansion Advantages Disadvantages References
TA B L E 3 SCT-related standards by international organisations.Association for the Advancement of Blood and Biotherapies; EBMT, European Group for Blood and Marrow Transplantation; EDQM, European Directorate for the Quality of Medicines and Healthcare; FACT, Foundation for the Accreditation of Cellular Therapy; ICH, International Council for Harmonisation; ISCT, International Society for Cell and Gene Therapy; ISSCR, International Society for Stem Cell Research; JACIE, Joint Accreditation Committee ISCT-Europe and EBMT; Ph.Eur, European Pharmacopoeia; SCT, stem cell-based therapy.